This proposal is focused on the effects of aging in the medial prefrontal cortex and associated behavior, with an emphasis on female rats and the role of estrogen and progesterone in cognitive aging. The proposal explores the hypothesis that the medial prefrontal cortex is one of the important sites for the cognitive decline associated with aging and for the actions of estrogen and progesterone on that decline. There are three issues that will be addressed here. One concerns the role of the medial prefrontal cortex in age-related cognitive decline. There has been considerable emphasis on the hippocampus in the rat because many of the cognitive behavioral tasks that show deficits in aged males are hippocampal dependent (eg, water maze, radial arm maze). The medial prefrontal cortex also is engaged in these tasks and is not as extensively studied, although there is neuro-anatomical evidence of aging in the cerebral cortex. The second topic is the characterization of aging in female rats. The literature on behavioral and neural effects of aging has, until recently, emphasized male rats. The many sex differences that have been documented in neural areas associated with cognition indicate that males and females enter the aging life phase with dimorphic nervous systems that may affect the aging process itself. The third issue concerns the efficacy of hormone replacement therapy including the mode of replacement (chronic vs cyclic hormones) on neural and behavioral aging. Ovariectomized, aged rats can provide a model for both chronic and tonic HRT on neural and behavioral aging. The recent results from the Women's Health Initiative make the studies proposed here of great clinical relevance. Hormone replacement therapy has become very common as the female population ages. It is essential to understand the effects of estrogen and progesterone on the aging process and how the effects of these hormones may be altered by different regimens of replacement. Another important aspect of clinical importance is the actions of ovarian steroids on the medial prefrontal cortex because the human analogue of this region is thought to be involved in schizophrenia. There are sex differences in the age and severity of onset of schizophrenia, and symptoms become exacerbated with menopause, which may indicate a protective role of estrogen and possibly progesterone for this region. Lastly, MRI in humans indicates changes in the volume of may neural areas with age. Exploring the cellular basis for these changes is not feasible in humans, but the aging rat can serve as a model for the types of cellular changes that underlie human aging.